The Development of Human Subject Research Policy at DHEW

As the largest funding source in the federal government for human subject
research, DHEW led the way in developing regulations aimed at protecting the
rights and welfare of subjects. The evolution of the regulations, which would
eventually be adopted on a government wide basis, was influenced by revelations
of unethical research, congressional reaction to the revelations, and concern
over public perception of such research. That regulations were eventually
adopted at all by DHEW was influenced by the political realities of the time
and the lack of congressional support for a standing regulatory body to oversee
human subject research, as had been recommended by an influential federally
appointed panel, the Tuskegee Syphilis Study Ad Hoc Panel. In a trade-off that
would have major influence on the future of human subject research oversight,
the proposed bill creating the standing regulatory body was withdrawn in
exchange for the National Research Act, establishing the National Commission,
and an understanding that DHEW would promulgate the aforementioned regulations.
This historical backdrop is outlined in the remainder of this chapter.

The Thalidomide Tragedy and the Congressional Requirement for Patient
Consent

In 1959 a Senate subcommittee chaired by Senator Estes Kefauver of Tennessee
began hearings into the conduct of pharmaceutical companies. Testimony
revealed that it was common practice for drug companies to provide samples of
experimental drugs, whose safety and efficacy had not been established, to
physicians, who were then paid to collect data on their patients taking these
drugs. Physicians throughout the country prescribed these drugs to patients
without their knowledge or consent as part of this loosely controlled research.
These practices and others prompted calls by Kefauver and other senators for an
amendment to the Food, Drug, and Cosmetic Act of 1938 to address the
injuriousness and ineffectiveness of certain drugs. In 1961 the dangers of new
drug uses were vividly exemplified by the thalidomide disaster in Europe,
Canada, and to a lesser degree, the United States.[5] Starting in late 1957, the sedative
thalidomide was given to countless pregnant women and caused thousands of birth
defects in newborn infants (most commonly, missing or deformed limbs). The
thalidomide disaster was widely covered by the television networks, and the
visual impact of these babies stunned viewers and caused Americans to question
the protections afforded those receiving investigational agents.

It is in large measure because of the thalidomide episode that the 1962
Kefauver-Harris amendments to the Food, Drug, and Cosmetic Act were passed,[6] requiring that informed consent be obtained in
the testing of investigational drugs.[7] While
such testing occurred mainly with patients, Congress carefully avoided
interfering in the doctor-patient relationship and in the process severely
reduced the effectiveness of the requirement. Consent was not required when it
was "not feasible" or was deemed not to be in the best interests of the
patient--both judgments made "according to the best judgment of the doctors
involved."[8] Despite their being limited in
scope, the Kefauver-Harris amendments were influential in advancing
considerations of protections of research subjects first within the DHEW and
later throughout the rest of the government.

NIH and PHS Develop a Uniform Policy to Protect Human Subjects

In late 1963, concerns were raised within NIH by Director James Shannon after
disturbing revelations about two research projects funded in part by the Public
Health Service and NIH. One was the unsuccessful transplantation of a
chimpanzee kidney into a human being at Tulane University, a procedure that
promised neither benefit to the recipient nor new scientific information. The
transplant was reportedly done with the consent of the patient, but without
consultation or review by anyone other than the medical team involved.[9]

The second was research undertaken in mid-1963 at the Brooklyn Jewish Chronic
Disease Hospital. There, investigators (the chief investigator, Dr. Chester M.
Southam was a physician at the Sloan-Kettering Cancer Research Institute, and
he received permission to proceed with the work from the hospital's medical
director, Dr. Emmanuel E. Mandel) had undertaken a research project in which
they injected live cancer cells into indigent elderly patients without their
consent. The research went forward without review by the hospital's research
committee and over the objections of three physicians consulted, who argued
that the proposed subjects were incapable of giving adequate consent to
participate.[10] The
disclosure of the experiment served to make both PHS officials like Shannon and
the Board of Regents of the University of the State of New York, which had
jurisdiction over licensure of physicians, aware of the shortcomings of
procedures in place to protect human subjects. They were further concerned
over the public's reaction to disclosure of the research and the impact it
would have on research generally and the institutions in particular. After a
review, the Board of Regents censured the researchers. They suspended the
licenses of Drs. Mandel and Southam, but subsequently stayed the suspension and
placed the physicians on probation for one year.[11] There were no immediate repercussions for
the hospital, Sloan-Kettering, the university, or PHS, but the case nonetheless
profoundly affected the subsequent development of federal guidelines to protect
research subjects.

To add to the ferment, NIH officials had closely followed the work of the
Law-Medicine Research Institute at Boston University, which issued survey
findings in 1962 showing that few institutions had procedural guidelines
covering clinical research.[12] And in the
year after both the above-mentioned cases came to light, the World Medical
Association issued its Declaration of Helsinki, which set standards for
clinical research and required that subjects give informed consent prior to
enrolling in an experiment.[13]
Thus national and world opinion on matters related to the ethics of human
subject research created a climate ripe for changes in policies and approaches
toward research ethics.

Concern over disturbing cases and the growing attention paid to research
ethics prompted NIH director James Shannon to create a committee in late 1963
under the direction of the NIH associate chief for program development, Robert
B. Livingston, whose office supported centers at which NIH-funded research took
place. The internal committee was charged with studying problems of inadequate
consent and the standards of self-scrutiny involving research protocols and
procedures. The committee was also to recommend a suitable set of controls for
the protection of human subjects in NIH-sponsored research. The Livingston
Committee recognized that ethically questionable research--exemplified by the
research at the Jewish Chronic Disease Hospital--could wreak havoc on public
perception, increase the likelihood of liability, and inhibit research.[14] These problems made it worthwhile to
reconsider central oversight--or lack thereof--for research contracted out.
However, the committee expressed concern over NIH taking too authoritarian a
posture toward research oversight and so argued that it would be difficult for
the agency to assume responsibility for ethics and research practices. When it
issued its report in late 1964, the committee did not recommend any changes in
the current NIH policies and, moreover, cautioned that "whatever NIH might do
by way of designating a code or stipulating standards for acceptable clinical
research would be likely to inhibit, delay, or distort the carrying out of
clinical research. . . ."[15] In deference to
physician autonomy and traditional regard for the sanctity of the
doctor-patient relationship, the report concluded that NIH was "not in a
position to shape the educational foundations of medical ethics. . . ."[16]

Director Shannon did not think the conclusions of the Livingston Committee
went far enough, feeling as he did that NIH should take a position of increased
responsibility for research ethics.[17]
Especially in light of the Jewish Chronic Disease Hospital case and its
implications for the NIH, both internally and in terms of public perception, he
felt that a stronger reaction was needed. Thus, despite the committee's
limited conclusions, Shannon and Surgeon General Luther Terry together decided
in 1965 to propose to the National Advisory Health Council (NAHC), an advisory
committee to the surgeon general of the Public Health Service,[18] that in light of recent problems, the NIH
should assume responsibility for formal controls on individual investigators.[19] At the NAHC meeting, Shannon argued for
impartial prior peer review of the risks research posed to subjects and
questioned the adequacy of the protections of the rights of subjects.[20]

The council's members mostly agreed with Shannon's concerns and three months
later issued a "resolution concerning research on humans" following Shannon's
broad recommendations and endorsing the importance of obtaining informed
consent from subjects:

Be it resolved that the National Advisory Health Council believes that Public
Health Service support of clinical research and investigation involving human
beings should be provided only if the judgment of the investigator is subject
to prior review by his institutional associates to assure an independent
determination of the protection of the rights and welfare of the individual or
individuals involved, of the appropriateness of the methods used to secure
informed consent, and of the risks and potential medical benefits of the
investigation.[21]

What this statement did not do, however, was explain what would count as
informed consent. The NAHC recommendations were accepted by the new surgeon
general, William H. Stewart, and in February 1966 he issued a policy statement
requiring PHS grantee institutions to address three topics by committee prior
review for all proposed research involving human subjects:

This review should assure an independent determination (1) of the rights and
welfare of the individual or individuals involved, (2) of the appropriateness
of the methods used to secure informed consent, and (3) of the risks and
potential medical benefits of the investigation.[22]

The 1966 PHS policy required that institutions give the funding agency a
written "assurance" of compliance, but like the NAHC recommendations, the
policy spoke strictly to the procedural aspects of informed consent and not to
its meaning and criteria. Substantive informed consent criteria were
established for research at the NIH Clinical Center shortly after the PHS
policy was issued, but this new policy applied only to intramural research,
that is, to research undertaken at the Clinical Center. The Clinical Center
policy was important as the first federal research policy with a specific
definition of what constituted informed consent requirements in the research
context. The inclusion of specific consent requirements in policies applying
to extramural research would not occur, however, until the mid-1970s.

The 1966 PHS policy is significant both for its recognition that
patient-subjects, like healthy subjects, should be included in the consent
provisions for federally sponsored human experimentation and for its attempt to
strike a balance between federal regulation and local control, which continues
to this day. Such a balancing continued the work begun by the AEC, in its
provision for local human use committees as a condition for the use of
AEC-supplied isotopes, and the DOD, in the provision for high-level review of
proposed experimentation. Although a landmark in the government regulation of
biomedical research, the 1966 policy was to be revised and changed throughout
the decade as biomedical research drew greater attention and informed consent
grew in importance.

While, from the outset, the PHS policy was revised periodically,[23] site visits by PHS employees to randomly selected
institutions revealed a wide range of compliance.[24] These site visits found widespread
confusion about how to assess risks and benefits, refusal by some researchers
to cooperate with the policy, and in many cases, indifference by those charged
with administering research and its rules at local institutions. Complaints of
overworked review committees and requests for clarification and guidance came
from research institutions all over the country.[25]

In response to continued questions about the scope and meaning of the policy,
DHEW in 1971 produced The Institutional Guide to DHEW Policy on Protection
of Human Subjects.[26] Better known as
the "Yellow Book" because of its
cover's color, this substantial guide contained both the requirements and
commentary on how the requirements were to be understood and implemented. The
guide provided that informed consent was to be obtained from anyone who "may be
at risk as a consequence of participation" in research--including both patients
and healthy volunteers.[27]

As the 1960s progressed, increased discussion of research practices appeared
in both professional literature and the popular press. One person who advanced
the debate in both arenas was Henry Beecher of Harvard Medical School.

Henry Beecher: The Medical Insider Speaks Out

Henry Beecher, as noted in chapter 2, was an active participant in
professional discussions of ethics in research during the late 1950s and early
1960s. In March 1965, Beecher focused attention on the issues at a conference
for science journalists sponsored by the Upjohn pharmaceutical company. There
Beecher presented a paper discussing twenty-two examples of potentially serious
ethical violations in experiments that he had found in recent issues of medical
journals.[28] (Among them was the Brooklyn
Jewish Chronic Disease Hospital study.) He explained this research had not
taken place "in a remote corner, but [in] . . . leading medical
schools, university hospitals, top governmental military departments,
governmental institutes and industry."[29] He
also acknowledged that his own conscience was not entirely clear: "Lest I seem
to stand aside from these matters I am obliged to say that in years gone by
work in my laboratory could have been criticized."[30] Beecher also explained the
consciousness-raising purpose of these revelations with stark clarity: "It is
hoped that blunt presentation of these examples will attract the attention of
the uninformed or the thoughtless and careless, the great majority of
offenders."[31]

In making this presentation to a group of journalists, Beecher was clearly
breaking with a professional expectation that such matters should be addressed
within the biomedical community. After some reservations on the part of
medical journals, the March 1965 paper having been rejected by at least the
Journal of the American Medical Association (JAMA), Beecher
published a revised version in the New England Journal of Medicine in
June 1966.[32] That article, like his
presentation at the conference,
indicted the entire biomedical research community and the journals that
published biomedical research results.

Beecher's efforts to focus professional, press, and therefore public
awareness
on the conduct of research involving human subjects met with some success. A
July 1965 article in the New York Times Magazine was headlined "Doctors
Must Experiment on Humans--But What Are the Patient's Rights?"[33] In February 1966, as the PHS issued its
first uniform policy for biomedical research, more headlines, this time in the
Saturday Review, asked, "Do We Need New Rules for Experimentation on
People?"[34] In July 1966, following
Beecher's article in the New England Journal of Medicine and an
editorial in JAMA, [35] another article declared "Experiments on
People--The Growing Debate."[36] Thus, by
the mid- to late 1960s, professional, governmental, and public attention was
all being drawn to issues of research on human subjects. Revelations of
purportedly unethical treatment of research subjects would not be over by this
time, but changes in policy largely driven by attention from so many corners
were beginning to move toward a more comprehensive approach to research
oversight.

Public Attention Is Galvanized: Willowbrook and Tuskegee

From 1956 to 1972 Dr. Saul Krugman of New York University led a study team at
the Willowbrook State School for the Retarded, on Staten Island, New York. The
study was not secret or hidden. (It was one of the twenty-two projects Beecher
discussed as ethically troublesome in his 1966 article.) The Willowbrook study
was discovered by the media beginning in the late 1960s[37] and was the subject of further discussion of
the case in separate places by Beecher,[38]
theologian Paul Ramsey,[39] and physician
Stephen Goldby.[40] Noting the high incidence
of hepatitis among the residents of the school, nearly all of whom were
profoundly mentally impaired children and adolescents, Krugman and his
colleagues injected some of them with a mild form of hepatitis serum. The
researchers justified their work on the grounds that the subjects probably
would have become infected anyway, and they hoped to find a prophylaxis for the
virus by studying it from the earliest stages of infection. Before beginning
the work, Krugman discussed it with many physician colleagues and sought
approval from the Armed Forces Epidemiological Board, which approved and funded
the research,[41] and the executive faculty of
the New York University School of Medicine, who approved the research. A
review committee for human experimentation did not exist in 1955,[42] but later, when such a committee was formed,
it too approved the research.

According to Krugman, the parents of each subject signed a consent form after
receiving a detailed explanation of the research, without any pressure to
enroll their child.[43] Some critics argued
that the content of the consent form was itself deceiving, since it seemed to
say that children were to receive a vaccine against the virus. Moreover,
charges of coercion arose. It is alleged that parents who enrolled their
children in the study were initially offered more rapid admission to the school
through the hepatitis unit and later found, due to overcrowding, that the only
route for admission of new patients was through the hepatitis unit.[44] Commentators further argued that the fault
in the doctors' study lay in their deliberate attempt to infect the children,
with or without parental consent, as opposed to studying the course of disease
in children who naturally became sick.

Soon after Willowbrook, another research project, the Tuskegee syphilis
study,
provoked widespread public outcry when it was revealed the study had exposed
people to unnecessary and serious harm with no prospect of direct benefit to
them. Beginning in 1932, PHS physicians sought to trace the natural history of
syphilis by observing some 400 African-American men affected by the disease and
another group of approximately 200 African-American men without syphilis
serving as controls. All the subjects lived in or around Tuskegee, Alabama.
Originally designed to be a short-term study in the range of six to eight
months, some investigators successfully argued that the potential scientific
value of longer-term study was so great that the research ought to go on
indefinitely. The subjects were enticed into the study with offers of free
medical examinations. Many of those who came from around the area to be tested
by "government doctors" had never had a blood test before and had no idea what
one was.[45] Once selected to be subjects in
the study, the men were not informed as to the nature of their disease or of
the fact that the research held no therapeutic benefit for them. Subjects were
asked to appear for "special free treatments," which included purely diagnostic
procedures such as lumbar punctures.[46]

By the mid-1940s it was becoming clear that the death rate for the infected
men in the study was twice as high as for those in the control group. This was
the period in which penicillin was discovered and soon after began to be used
to treat syphilis, at least in its primary stage. The study was reviewed by
PHS officials and medical societies and reported by a number of journals from
the early 1930s to 1970. In the 1960s a growing number of criticisms began to
appear, although the study was not stopped until 1973.

Thus, men with a confirmed disease were not told of their diagnosis and were
deceived into participating in the study under the guise of its being
therapeutic for unspecified maladies. In addition to exposing the subjects to
the additional harms of participation in the study, the false belief that
treatment was being administered prevented subjects from otherwise seeking
medical care for their disease. As at Willowbrook, a justification given after
the fact for the research was that the disease had appeared in a way that was
natural and inevitable and that the study would be of immense benefit to future
patients.[47] Over this forty-year history,
at least 28 participants died and approximately 100 more suffered blindness and
insanity from untreated syphilis before the study was stopped.

In 1972, an account of the study was published on the front page of the
New
York Times.[48] In response, DHEW
appointed the Tuskegee Syphilis Study Ad
Hoc Panel to review the Tuskegee study as well as the department's policies and
procedures for the protection of human subjects. The work of the ad hoc
panel--which consisted of physicians, a university president, a theologian, an
attorney, and a labor representative--contributed in large measure to the
passage of the first comprehensive regulations for federally sponsored human
subjects research. One member of the ad hoc panel who is also a member of the
Advisory Committee, Jay Katz, expressed his dismay over the unwillingness or
incapacity of society to mobilize the necessary resources for "treatment" at
the beginning of the study and the deliberate efforts of the investigators to
"obstruct the opportunity for treatment."[49]

Despite the fact that the PHS Policy for the Protection of Human Subjects had
been in place for six years by the time the Tuskegee study was revealed, it was
exposed by a journalist rather than by a review committee. Although an
institutional committee had allegedly reviewed the Tuskegee study, the study
was not discontinued until after the recommendation of the ad hoc panel.[50] The human rights abuses of the Tuskegee
study demonstrated the need for both prior and ongoing review, in that the
study was undertaken before prior review requirements were in place, and the
prevailing review policies during the period of the study were so flawed that
the study was allowed to continue.

As a result of their deliberations, the ad hoc panel found that neither DHEW
nor any other agency in the government had adequate policies for oversight of
human subjects research. The panel recommended that the Tuskegee study be
stopped immediately and that remaining subjects be given necessary medical care
resulting from their participation.[51] The
panel also recommended that Congress establish "a permanent body with the
authority to regulate at least all federally supported research involving human
subjects."[52] In summary, the panel
concluded that despite the lessons of Nuremberg, the Jewish Chronic Disease
Hospital case, and the Declaration of Helsinki, human subject research
oversight and mechanisms to ensure informed consent were still inadequate and
new approaches were needed to adequately protect the rights and welfare of
human subjects.

Congressional Response to Abuses of Human Subjects: The National Research
Act

Public attention to abuses such as those inflicted on the subjects of the
Tuskegee study increased during the late 1960s and early 1970s. Following the
initial revelations about the Tuskegee syphilis study, several bills were
introduced in Congress to regulate the conduct of human experimentation. In
February 1973 Senator Edward Kennedy held hearings on these bills;[53] the Tuskegee study;
experimentation with prisoners, children, and poor women; and a variety of
other issues related to biomedical research and the need for a national body to
consider the ethics of research and advancing medical technology.[54] After the hearings, Senator Kennedy
introduced an unsuccessful bill to create a National Human Experimentation
Board, as recommended by the Tuskegee Syphilis Study Ad Hoc Panel. When it
became clear, however, that the bill would not be successful, Senator Kennedy
introduced the bill that would become the National Research Act, endorsing the
regulations about to be promulgated by DHEW and establishing the National
Commission for the Protection of Human Subjects of Biomedical and Behavioral
Research, in return for DHEW's issuance of human subject research
regulations.[55] The trade-off was clear: no
national regulatory body in return for regulations applying to the research
funded or performed by the government agency responsible for the greatest
proportion of human subject research. This meant that the goal of oversight of
all federally funded research would not be achieved and that whatever
oversight did exist was left to the funding agencies rather than an independent
body.

On May 30, 1974, DHEW published regulations for the use of human subjects in
the Federal Register. [56] These regulations required that each grantee
institution form a committee (what became known as an institutional review
board, or IRB) to approve all research proposals before they were passed to
DHEW for funding consideration. These committees were charged with reviewing
the safety of the proposals brought to them as well as the adequacy of the
informed consent obtained from each subject prior to participation in the
research. Additionally, the regulations defined not only the procedure for
obtaining informed consent but substantive criteria for it as well. Shortly
after the announcement of the DHEW regulations, in July 1974, the National
Research Act was passed, and with it came the establishment of the National
Commission.[57]

The National Commission--charged with advising the secretary of DHEW (though
the National Research Act did not require the secretary to follow the
commission's recommendations)--existed over the next four years and published
seventeen reports and appendix volumes. During its tenure, the commission did
pioneering work as it addressed issues of autonomy, informed consent, and
third-party permission, particularly in relation to research involving
vulnerable subjects such as prisoners, children, and people with cognitive
disabilities. It was also charged with examining the IRB system and procedures
for informed consent, as background for proposing guidelines that would ensure
that basic ethical principles were instituted in the research oversight system
and in research involving vulnerable populations.

In the course of its deliberations, the commission identified three general
moral principles--respect for persons, beneficence, and justice--as the
appropriate framework for guiding the ethics of research involving human
subjects. These three are known as the Belmont principles because they
appeared in The Belmont Report, one of the commission's major
publications.[58]

The National Commission was required to examine the "nature and definition"
of
informed consent as well as the "adequacy" of current practices. In its
reports, the commission decisively argued that the basic justification for
obligations to obtain informed consent is the moral principle of respect for
persons. This emphasis on respect for persons meant a great premium was put on
autonomous decision making by the research subject, an emphasis that continues
to the current day.

While it may not have been the intent of those who sponsored it, the National
Research Act--because it was limited to DHEW-funded research--did not ensure
that all federally sponsored research would be subject to requirements for
informed consent and prior review. Nonetheless, by this time, as described
below, published policies within the DOD, the AEC, the VA, and NASA did meet
these requirements.

The passage of the National Research Act and the promulgation of DHEW's
regulations were important milestones in the development of federal standards
for the protection of human subjects of research. They represented the first
national recognition of the need to protect human subjects. Moreover, they
attempted to provide for that protection through the IRB requirement and
establishment of the National Commission. The Advisory Committee's charter
requires that it examine the standards for research between 1944 and 1974.
These two landmark events in 1974 ushered in a new era in which the conduct and
oversight of biomedical experimentation with humans remained a topic of
national scrutiny and debate. Eventually, the approaches required by the 1974
DHEW regulations would be applied to nearly all federally sponsored human
research, as described in chapter 14.